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Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage. Great progress has been made in understanding the important roles of various G protein-coupled receptors in the regulation of pain transmission. However, many important questions remain uncertain about the precise signal transduction mechanisms. This review focuses opioid receptor and CXC receptor 4 on the effects and mechanisms of pain. Taken together, chemokines and their receptors are potential targets for the development of novel pain management and therapy.